Bone Mineral Drugs Flashcards
What is plasma calcium tightly regulated at?
What are components of plasma calcium?
- plasma calcium tightly regulated at 2.5 mM = 5mEq/L = 10mg/dl
- 50% ca is free, 40% bound to albumin and 10% complexted with citrate or phosphtate etc.
- what are the major sites of action for blood calcium regulation?
- Bone
- GI- total dietary intake of ca is about 1000 mg/day and excretion in feces is about 900mg/day
- Kidney- excretion of calcium is about 100mg/day
Function of PTH, site of synthesis, action?
- function is to increase plasma ca
- made by parathyroid glands, hence the name duh
- acions include: increased bone resorption, increased kidney reabsorption, increased active form of vitamin d.
**calcium sensing GPCR allow both PTH and calcitonin secreting cells to respond to extracellular calcium. These are found in parathyroid glands AND parafollicular cells of thyroid.
** activation of these calcium receptors –> activate PLC–> DAG and IP3
**Inhibition of adenylate cyclase –> suppress intracellular cAMP
Function, site of synthesis and actions of Calcitonin?
- opposite of PTH, decreased plasma Ca
- made in parafollicular cells of thyroid (also made in other tissues like lung and intestinal tract)
- actions: decrease bone resorption, decrease kidney reabsorption, decrease active form of vitamin D.
Function, site of synthesis, actions of Calcitriol (vitamin 1, 25 dihydroxy-d3?
- Function is to increase plasma Ca
- Made in skin and blood
- actions: increase calcium uptake from GI (most important phsiologic action)
- pharmacologic actions: increse kidney reabsorption, increase bone resorption (paradoxical. increasing doses promote resorption. calcium can reverse this effect).
What can lead to calcium homeostasis loss?
- estrogen deficiency
- glucocoritcoid excess
- growth hormone deficiency
- insulin deficiency
- primary hypoparathyroidism
- cancer
What is the response to low plasma Ca?
- detectd by parathyroid –> increased PTH synthesis
- increased absorption of calcium by kidney and increased synthesis of calcitrol and increased resorption of bone
** more calcitriol results in increased GI absorption of calcium
what is the response to high plasma calcium?
- detected by parafollicular cells of thyroid –> calcitonin synthesis
- decresed synthesis and secretion of PTH
- decreased resorption of bone
- shift to inactive form of vitamin D
- decreased PTH cause increased excretion of Ca.
PTH MOA?
- bind plasma membrane receptor –> activate adenylate cyclase
–> inrease cAMP –> cAMP activates protein kinases –> action results in increased urinary cAMP (a test for parathyroid gland function)
MOA of teriparatide and clinical use?
it is a hrPTH 1-34 that directly stimulates bone formationa nd acts through PTH receptors
- may stimulate IGF-1
- excess cause bone resorption but low doses increase bone formation without stimulating resorption
- clinical uses for women with osteoporosis after bisphosphanate therapy
MOA of reloxifene and clinical use?
Selective estrogen recpetor modulator that is a estrogen agonist effect in bone
- estrogen antagonist effects in breast and endometrium
**beneficial effects of estrogen without stimulating breast cancer and use din osteoporosis in postmenopausal women
Side effects of raloxifene??
- hot flashes, leg cramps, thromboembolism!
MOA of Denosumab and clinical applicaitons?
- monoclonal antibody to RANKL
- block stimulation of osteocyte formation by RANKL and decrease osteoporosis
- increase bone mass in patietns with breast or prostate cancer.
Function of FGF23 and what produces it?
- inhibit production of 1, 25 OH2D3 so opposes PTH in kidney
- produced by osteoclast and osteoblasts
MOA calcitonin and thearapeutic use?
- bind plasma membrane receptor to inhibit bone resorption
- decreases ruffled border surface area on osteoclasts
NOT a global inhibitor of PTH
- **DIRECT RENAL effects
**used for hyperclacemia and paget’s disease osteoporosis (nasal spray)
duration of action for calcitonin
- short term treatment of hypercalcemia
- development of antibodies occur with long ter use even with hCT
- prednisone can be used for hypercalcemia but it takes 1 to 2 weeks to work
Calcitriol MOA
- stimulates Ca and phosphate absorption in the small intestine
- primary effect is th induce synthesis of calbinding (famil of ca binding protein)
- bind to transcription factor to increase mRNA, protein synthesis
- has additional effects in increasing uptake of Ca form intestine in duodenum
calcitriol therapeutic exaples and clinical use?
- calcitriol can be used for rickets, osteomalacia, hypoparathyroidism, and in prevention and treatment of osteoporosis
- cholecalciferol = vitamin d3, ergosterol, ergocalciferol = vitamin d2, 25-OH cholecalciferol all used for vitamin d deficiency
Calcitriol analogs and clinical uses?
- calcipotriol, used in tx of psoriasis (more effectiv than GC)
- dihydrotachysterol- used for osteoporosis
- paricalcitrol- reduce PTH secretion
- 22-oxacalcitriol- suppress PTH gene expression
**last two for patients with increased PTH
MOA of bisphosphonates, drug examples and clinical use?
- suppress activity of osteoclasts and inhibits bone resorption; very effective at killing osteoclasts
- used for osteoporosis and paget’s disease
- first gen: etidronate
- 2nd gen: alendronate, pamidronate, ibandronate
- 3rd gen: risedronate, zoledronate
**with every generation, drugs becoem more and more potent.
Side effects of bisphosphanates?
- like denosumab, can cause osteonecrosis of the jaw (more common with 3rd gen and pts with cancer after prolonged therapy)!
-bone under teeth exposed, swelling, loose teeth, esophageal irritation
Which drugs are useful in reversing lymphoma induced hypercalcemia?
- glucocorticoids- they antagonize Ca uptake in intestine and are a common cause of osteoporosis in adults!!
What replacement therapy has been shown to prevent osteoporosis? Side effects?
- estrogen
- increased risk of thrombosis
Calcimimetic MOA, drug example, and clinical use?
- bind and activate calcium- sensing receptors
- cinacalcet- hyperparathyroidism in patietns with parathyroid carcinoma
**allows PTH suppression at lower Ca2+ concentration so it is more sensitive to calcium.
which antibiotic has been used for paget’s disease and hypercalcemia for many years?
- plicamycin but it is seldom used now. It is used for short term tx of hypercalcemia still
strontium ranelate MOA, clinical use, side effects?
- blocks differentiation of osteoclasts and promotes apoptosis
- promotes bone formation via osteoblasts –> increase bone mineral density and decrease fractures
- used for osteoporosis and osteoarthritis
- side effects: venous thromboembolisms, and heart attack!!!
What’s the use of Fluoride as tx? Side effects?
- long used for dental caries prevention
- F bind calcium and can be used to prevent blood clotting
- side effects from toxicity: osteosclerosis (hydroxyapatite replaced by fluoroapatite)
and mottled enamel (fluorosis)
